Compositions and methods for treating heart failure

Abstract

In certain aspects, the present disclosure relates to methods of treating, preventing, and reducing the severity or progression of heart failure or one or more complications of heart failure. For example, the disclosure provides various BMP antagonists, such as ActRIIA polypeptides, ActRIIB polypeptides, BMPRII polypeptides, ALKI polypeptides, endoglin polypeptides, BMP 10 propeptide proteins and Fc fusion proteins thereof as well as anti-BMP9 antibodies, for treating, preventing and reducing the severity or progression of heart failure or one or more complications of heart failure.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of priority from U.S. Provisional Application No. 62 / 455,266, filed Feb. 6, 2017. The specification of the foregoing application is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0002]It has been estimated that over five million people suffer from heart failure in the United States alone. Statistics from the American Heart Association also suggest that new cases of heart failure are diagnosed at a rate of about 550,000 each year. Of the newly diagnosed patients fifty percent are likely to die within five years from the initial diagnosis. Of course, these numbers do not account for the number of patients in other countries who also suffer from heart failure. Given these numbers, it is clear that heart failure is a significant human crisis.[0003]Heart failure is a condition that is characterized, in part, by a reduced ability of the heart to circulate blood through the body. ...

AI Technical Summary

Benefits of technology

[0005]In part, the data presented herein demonstrates that BMP antagonists (inhibitors) can be used to treat heart failure. For example, it was shown that a soluble BMP10 propeptide (BMP10pro) polypeptide can be used to prevent or reduce the severity of cardiac hypertrophy, cardiac remodeling, and cardiac fibrosis as well as improve cardiac function in a transverse aortic constriction (TAC) heart failure model. Moreover, BMP10pro treatment increased survival time of heart failure patients. In additional studies, the BMP10pro polypeptide was shown to prevent or reduce the severity of cardiac hypertrophy, cardiac remodeling, and cardiac fibrosis in a myocardial infarction (MI) heart failure model as well as increase survival time in these patient. Binding studies demonstrated that BMP10pro polypeptides have high affinity and can antagonize activity of BMP10. In addition, data of the disclosure show that BMP10pro polypeptides bind with high affinity to BMP9, BMP6, and BMP3b, and to a lesser extent BMP5. Furthermore, the experiments described herein demonstrate than a soluble endoglin polypeptide may be used to treat heart failure. For example, treatment with an endoglin polypeptide reduced the severity of cardiac hypertrophy, reduced cardiac function, and cardiac fibrosis in a TAC heart failure model as well as reducing the severity of cardiac hypertrophy, cardiac remodeling, reduced cardiac function, and cardiac fibrosis in a MI heart failure model. In addition, treatment with the endoglin polypeptide increased survival time of patient in both the TAC and MI heart failure models. In addition, data of the disclosure show that endoglin polypeptides bind with high affinity to BMP9 and BMP10. Thus, the disclosure establishes that antagonists of BMP signaling (e.g.,

Problems solved by technology

In some embodiments, the risk of death of a patient is from any cause (all-cause mortality).

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